Mechanostimulatory Platform for Improved CAR T Cell Immunotherapy

Abstract Chimeric Antigen Receptor T (CAR T) cell immunotherapy has revolutionized cancer treatment, yet it is hindered by rapid T‐cell exhaustion caused by uncontrolled activation during CAR generation. Leveraging insights into T‐cell mechanosensing, a novel mechanostimulatory platform is engineered for T‐cell activation based on an antigen‐carrying surface with controlled elasticity and nanotopography. The platform is designed to optimize and balance T‐cell exhaustion, proliferation, and CAR expression. It enhances the differentiation of T cells into the central memory subset, which is crucial for the persistence of CAR T cell therapy's anticancer effects. The platform produces CAR T cells with higher antitumor efficacy, as validated through ex vivo experiments, and with higher in vivo persistence and ability to suppress tumor proliferation, as compared to CAR T cells generated by standard protocols. RNA‐seq analysis confirmed an increased transcriptional signature of central memory T cells. Furthermore, this platform completely eliminates T‐cell toxicity associated with the non‐viral transfection process typically observed with standard activation methods. This platform presents a promising pathway for improving the efficiency and safety of CAR T cell therapy.